1. Top of page
  3. References

Many failures in the treatment of patients with hepatocellular carcinoma (HCC) are the result of incorrect tumor staging. Despite progress in statistical methods and gains in knowledge of the natural history of liver cancer, the ideal staging system for HCC has yet to be determined. This is in part because of the epidemiologic and clinical heterogeneity of the tumor, which depends mainly on the interplay between constitutional and environmental risk factors for the tumor and the presence and severity of the underlying liver disease. Difficulties in developing staging systems for HCC also have originated from the differences in expertise and treatment algorithms adopted in different centers worldwide, thus raising the issue of whether it is worthwhile to attempt to reach consensus on a single model for staging HCC. Indeed, to our knowledge, all staging systems reported to date tend largely to reflect the demographic features of the patients seen locally, the center's resources, the professional attitudes of the physicians involved, and the unavoidable bias of patient selection. The Consensus Statement on Staging for Hepatocellular Carcinoma, published elsewhere,1 provides a negligible contribution to the clinical management of patients with HCC because it endorses staging systems that stratify patients with different prognoses but has no link with treatment indications or treatment outcome.

In our experience, the primary purpose of staging a progressive tumor such as HCC is to distinguish those patients with a potentially curable disease from those with more advanced disease and a dismal outlook, for whom curative treatments are not applicable. Therefore, we disagree with the Consensus Statement that the Cancer of the Liver Italian Program (CLIP) staging system2 is the staging system of choice for patients with HCC because we believe it to have suboptimal sensitivity for tumor invasiveness (patients with a CLIP score of 0 may have from 0–50% of their liver replaced by the tumor) and to be definitively skewed toward more severely affected patients whose disease is not amenable to curative treatment. As a consequence, too many patients with a CLIP score of 0 will not meet the currently accepted criteria for surgical and percutaneous interstitial treatments that have been proven to be efficacious in patients in whom there is 1 cancerous node measuring < 5 cm in size. Conversely, a score of 1 includes patients with up to 3 cancerous nodes measuring < 3 cm in size (who have a potentially good prognosis because they fit the criteria for liver transplantation and percutaneous interstitial therapies) with those patients who have extended liver involvement by the tumor (whose poorer prognosis means they stand little chance of receiving curative treatment). Vascular invasiveness by the tumor and tumor cell differentiation are reported to be the dominant predictors of survival in surgically treated patients,3 and are reliably assessed by surgical specimens only. The size and number of cancerous nodes that we believe to be the best clinical surrogates of the above cited pathologic predictors4 are not properly weighted by the CLIP score. We also hesitate to endorse the American Joint Committee on Cancer TMN staging system as an adequate approach for predicting survival after tumor resection or liver transplantation. The TNM classification does not take into proper account the significant prognostic value of liver impairment in patients with HCC.5, 6

In the near future, genomics and proteomics could help in implementing the staging of HCC patients because different pathways of liver cell carcinogenesis exist that are linked to the expression of different cell genes and are believed to be correlated with different outcomes of the disease.7


  1. Top of page
  3. References
  • 1
    Henderson JM, Sherman M, Tavill A, Abecassis M, Chejfec G, Gramlich T. AHPBA/AJCC consensus statement on staging for hepatocellular carcinoma: consensus statement. HPB 2003; 5: 243250.
  • 2
    Cancer of the Liver Italian Program (CLIP) Investigators. A new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients: the Cancer of the Liver Italian Program (CLIP) investigators. HEPATOLOGY 1998; 28: 751755.
  • 3
    Jonas S, Bechstein WO, Steinmuller T, Herrmann M, Radke C, Berg T, Settmacher U, et al. Vascular invasion and histopathologic grading determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis. HEPATOLOGY 2001; 33: 10801086.
  • 4
    The Liver Cancer Study Group of Japan. Predictive factors for long term prognosis after partial hepatectomy for patients with hepatocellular carcinoma in Japan. Cancer 1994; 74: 27722780.
  • 5
    Marsh JW, Dvorchik I, Bonham CA, Iwatsuki S. Is the pathologic TNM staging system for patients with hepatoma predictive of outcome? Cancer 2000; 88: 538543.
  • 6
    Llovet JM, Bruix J, Fuster J, Castells A, Garcia-Valdecasas JC, Grande L, Franca A, et al. Liver transplantation for small hepatocellular carcinoma: the tumor-node-metastasis classification does not have prognostic power. HEPATOLOGY 1998; 27: 15721577.
  • 7
    Laurent-Puig P, Legoix P, Bluteau O, Belghiti J, Franco D, Binot F, Monges G, et al. Genetic alterations associated with hepatocellular carcinomas define distinct pathways of hepatocarcinogenesis. Gastroenterology 2001; 120: 17631773.